Mycobacterium tuberculosis (M.tb)-induced tuberculosis (TB) remains the leading morbidity and mortality worldwide, and the magnitude of the problem continues to grow, due in part to HIV pandemics. Sustained increases in cases of multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) strains are making TB extremely difficult to treat and globally control. Since drug resistance is likely to increase, there is a pressed need to develop new vaccines or immunotherapeutics. We have recently shown that IL-2 treatment of macaques can induce remarkable expansion of CD4+CD25(high)Foxp3+ T regulatory cells (Treg) in systemic and respiratory sites, and more importantly confers apparent homeostatic protection against TB lesions. This surprising finding suggests that Treg can function in vivo as homeostatic regulator against TB, far beyond simple inhibition of immune responses. Based on this novel observation, we hypothesize that IL-2-expanded Treg can orchestrate or balance host responses and suppress M.tb-mediated inflammatory events, leading to no or mild TB lesions, whereas IL-2-activated T effector cells producing IFN?;or cytotoxic cytokine may help to limit M.tb replication and dissemination. To test this hypothesis, we will: I. Perform mechanistic studies to determine a critical role of IL-2-expanded Foxp3+ Treg in anti-TB immunity in macaques. II. Determine if intermittent IL-2 treatments during chronic active M.tb infection can sustain Treg expansion, down-regulate TB-driven inflammatory events or associated M.tb replication, and confer immunotherapeutics against severe TB lesions and/or TB cavities. III. Examine kinetics and function of Treg during SHIV-induced reactivation of latent M.tb co-infection, and determine if combined ART and intermittent IL-2 treatment can expand Treg and ?d, CD8 T effector cells, and confer immunotherapeutics against AIDS-related reactivation TB. PUBLIC HEALTH RELEVANCE: This project is proposed based on our recent novel observation that cytokine IL-2 treatment of macaques induces remarkable expansion of CD4+Foxp3+ T regulatory cells (Treg), and confers apparent protection against tuberculosis disease or tissue damages. Studies will elucidate immune mechanisms for IL-2-induced anti-tuberculosis immunity, and explore IL-2-based treatment modalities for tuberculosis and AIDS-related tuberculosis. Findings will exert sustained, long-term impact on tuberculosis research and provide potential alternative treatment for tuberculosis, multi-drug resistant tuberculosis, and AIDS-related tuberculosis.